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#tweetorial 🧵
➡️Ph-like ALL / BCR-ABL1-like ALL

👉A provisional entity in the 2016 World Health Organization classification of acute leukemia 🩸🩸
👉Gene expression 🧬signature similar to Ph-positive ALL but lacks the BCR-ABL1 translocation
@NancyArthurPhD

➡️Originally defined by gene expression 🧬profiling in 2009 by 2 groups
👉Children's Oncology Group (COG) and St. Jude Children's Research Hospital (referred to as Ph-like ALL) 👉Dutch Childhood Oncology Group (referred to as BCR-ABL1-like ALL) – DCOG/COALL

👉The differences in the approaches are outlined in the figure; more on the gene expression 🧬 signatures and diagnostic conundrums later!

➡️Prevalence
👉Prevalence appears to increase 📈with age and peaks in young adults
👉More common in males👨♂️

➡️Outcome
👉Ph-like ALL is consistently associated with elevated WBC count
👉high rates ⚡️of end-induction MRD
👉📈increased risk of treatment failure and relapse 🔁

➡️Genetic 🧬subtypes in Ph-like ALL
👉Constitutes a heterogeneous group of genetic alterations rather than a single molecular aberration or chromosomal translocation
👉Includes rearrangements, copy number alterations, and sequence mutations

👉All these activate tyrosine kinase or cytokine receptor signalling 📶
👉Broadly classified into rearrangements that dysregulate the JAK-STAT pathway, ABL class rearrangements and a small miscellaneous proportion

➡️JAK-STAT pathway: CRLF2 rearrangements
👉Cytokine receptor-like factor 2 (CRLF2) is the receptor for TSLP.
👉Thymic stromal lymphopoietin (TSLP) plays key roles at several points in normal hematopoietic cell development and function

👉Dysregulated expression of and/or signalling 📶 by TSLP has been seen in a wide variety of inflammatory 🔥 settings, including asthma, allergy, and cancer🦀
👉CRLF2 dysregulation results in constitutive JAK/STAT activation and cytokine-independent growth

👉About 50% of CRLF2 positive cases also have a JAK mutation

JAK-STAT pathway: CRLF2 rearrangements
👉5–15% of all B-ALL cases, 50% of Ph-like B-ALL and 50–60% of Down syndrome (DS)-associated B-ALL show overexpression of CRLF2 due to 👇
A.IGH-CRLF2 fusion due to a t(X;14) or t(Y;14)

B. Interstitial deletion of the pseudoautosomal region (PAR1) of chromosomes X or Y 🧬places CRLF2 under control of the noncoding P2RY8 or CSF2RA promoters to drive fusion transcript expression
C.Rarely due to a point mutation in the CRLF2 gene

👉The presence of CRLF2 rearrangements is associated with Hispanic ethnicity

➡️JAK-STAT pathway 🛣️: JAK2 gene rearrangements
👉Rearrangements and gain-of-function mutations involving the Janus kinase (JAK) family kinases have been reported in ~10% Ph-like B-ALL
👉~ 20 JAK2 5‘-partner genes with the 3’ JAK2 kinase gene have been reported to date.

👉The chimeras include the carboxyl-terminal portion of JAK2 with its tyrosine kinase domain intact joined in-frame to the amino-terminal portion of the partner protein.

👉Result in STAT5 activation and growth factor independence, making cells expressing these fusions amenable to JAK2 inhibitors

➡️JAK-STAT pathway: Erythropoietin receptor gene rearrangements
👉~9% of Ph-like B-ALL and ~1% of all B-ALL cases
👉EPOR forms a homodimeric receptor for erythropoietin, and EPOR signalling is required for normal erythroid development

👉Normal B-progenitor cells do not express EPOR, It has been described in ETV6-RUNX1-positive B-ALL and in rare cases of B-progenitor ALL with the t(14;19).

➡️JAK-STAT pathway: EPOR gene dysregulation
👉Dysregulated by insertion of EPOR next to IgH enhancer; insertion into IGK locus;t(14;19); inversion 19.

👉EPOR rearrangements result in overexpression of EPOR protein that is truncated at its carboxy-terminal end and has lost its -ve regulatory domains

👉Same residues that are mutated in primary familial congenital polycythemia (OMIM #133,100), an inherited disorder in which germline EPOR frameshift and nonsense mutations truncate the carboxy-terminal end of the receptor.

👉Deregulated EPOR expression results in hypersensitivity to EPO, enhanced JAK-STAT signalling, and sensitivity to JAK-STAT inhibition

➡️ABL-class translocations
👉Translocations involving the pro-oncogenes ABL1, ABL2, CSF1R and PGDFRA/B are evident in about 15% of Ph-like ALL cases.

👉Mutually exclusive with CRLF2 and JAK-STAT mutations but, as in other Ph-like subgroups, are often concomitantly present with IKZF1 mutations/deletions

👉Patients with ABL-activating translocations usually respond poorly to therapy, continue to have a measurable residual disease (MRD) after induction and should be treated with ABL inhibitors

➡️Other recurrent mutations in Ph-like ALL
👉15-20% of Ph-like ALL cases exhibit
📌RAS pathway activating mutations or deletions (KRAS, NRAS, NF1, PTPN11)
📌Copy number aberrations in genes involved in B-cell development (IKZF1, PAX5, EBF1, and ETV6)

📌Cell cycle regulators (CDKN2A/B, TP53, BTG1, and RB1)
👉 5% of Ph-like ALL cases harbour gene fusions or mutations involving NTRK3, BLNK, DGKH, PTK2B, FLT3, FGFR1, TYK2 and SH2B3

➡️Diagnosis of this high-risk subtype is vital for improved therapeutic intervention
👉Challenges:
📌Heterogeneous genomic landscape
📌Cytogenetically cryptic alterations identified in Ph-like ALL
📌No clear consensus on the definition of Ph-like ALL gene expression profile

👉Several approaches have been used by various groups and is summarized in the figure:

➡️Tiered approach for diagnosis of Ph-like ALL
📌A robust diagnostic strategy for Ph-like ALL will depend on the technical expertise available as well as the cost of the test and turnaround time.

📌The subset tested can be B-other ALL/patients who are end of induction MRD positive in resource-constrained settings where all patients cannot be screened.
📌A systematic tiered approach for high–risk B-ALL is illustrated below (Genes 2021, 12, 687)👇

👉The 1st step can flow for CRLF2 overexpression followed by FISH for IgH /CRLF2 and RT-PCR for P2RY8-CRLF2 in patients with high CRLF2.

👉In patients with low CRLF2 either a fusion panel testing can be performed or a stepwise FISH strategy using probes for various ABL class genes can be included.
👉In patients who test negative, RNA-seq /WGS can be done.

➡️Rationale for targeted therapy in Ph-like ALL
👉Majority of the genes dysregulated converge in two pathways – ABL/ JAK-STAT ( See figure from Genes 2021, 12, 687)

👉Successful treatment of Ph-positive ALL by the addition of TKI as well as anecdotal reports and retrospective trials has led to several clinical trials assessing the efficacy of TK inhibitors as well as JAK-STAT pathway inhibitors ( see table)

👉Next-generation of Ph-like ALL trials may incorporate immune therapies based on studies combining it with TKI (N. Engl. J. Med. 2020, 383, 1613–1623, Blood 2021, 137, 471–484)

➡️Clinical trials evaluating the efficacy of ABl1 class and JAK-STAT pathway inhibitors
👉Several large international trials are underway to test the efficacy of incorporation of various ABL1 class and JAK-STAT pathway inhibitors in treatment regimens can improve outcome 👇

END OF TUTORIAL!!

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